Nanoenabled IL-15 Superagonist\nvia Conditionally Stabilized\nProtein–Protein Interactions Eradicates Solid Tumors by Precise\nImmunomodulation

Protein complexes are crucial structures that control\nmany biological\nprocesses. Harnessing these structures could be valuable for therapeutic\ntherapy. However, their instability and short lifespans need to be\naddressed for effective use. Here, we propose an innovative approach\nbased on a functional polymeric cloak that coordinately anchors different\ndomains of protein complexes and assembles them into a stabilized\nnanoformulation. As the polymer–protein association in the\ncloak is pH sensitive, the nanoformulation also allows targeting the\nrelease of the protein complexes to the acidic microenvironment of\ntumors for aiding their therapeutic performance. Building on this\nstrategy, we developed an IL-15 nanosuperagonist (Nano-SA) by encapsulating\nthe interleukin-15 (IL-15)/IL-15 Receptor α (IL-15Rα)\ncomplex (IL-15cx) for fostering synergistic transpresentation in tumors.\nUpon intravenous administration, Nano-SA stably circulated in the\nbloodstream, safeguarding the integrity of IL-15cx until reaching\nthe tumor site, where it selectively released the active complex.\nThus, Nano-SA significantly amplified the antitumor immune signals\nwhile diminishing systemic off-target effects. In murine colon cancer\nmodels, Nano-SA achieved potent immunotherapeutic effects, eradicating\ntumors without adverse side effects. These findings highlight the\ntransformative potential of nanotechnology for advancing protein complex-based\ntherapies.